Pazopanib is a tyrosine kinase indicator, belonging to a class of substituted pyrimidine derivative. It is designated chemically as 5-[[4-[(2, 3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl benzenesulfonamide, is represented by the following structure of Formula I:

Pazopanib is marketed as hydrochloride salt by Glaxosmithkline under the trade name VOTRIENT® is tyrosine kinase inhibitor and indicated for the treatment of patients with advanced renal cell carcinoma (RCC) and treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.
U.S. Pat. No. 7,105,530 (“the '530 patent”), U.S. Pat. No. 7,262,203 (“the '203 patent”) and U.S. Pat. No. 8,114,885 (“the '885 patent”) discloses a variety of pyrimidineamines and their derivatives such as Pazopanib, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof.
The process disclosed in the '530 patent is schematically represented as follows:

Patent publication No. WO 2011/050159 (“the '159 publication”) disclosed process for preparation of Pazopanib hydrochloride, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dichloropyrimidine of Formula B in a solvent like industrial methylated sprit and specific reaction conditions like, in presence of a base, sodium bicarbonate having a particle size distribution of >250 μm or 50 to 150 μm selected to ensure that the pH of the reaction mixture is less than 7 for the reaction time period not more than 300 min to obtain N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine of Formula II. The compound of Formula II was methylated in presence of a methylating agent in an organic solvent like dimethylformamide by using specific reaction conditions like, in presence of a base i.e. Potassium carbonate having a particle size distribution D99 of >300 μm or D99 of <200 μm selected to ensure that the reaction time needs to reduce the starting material to less than 2% in less than 8 hrs to obtain N-(2-chloropyrimidin-1-yl)-N-2,3-trimethyl-2H-indazol-6-amine of Formula III. The resultant methylated compound was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of 4M HCl and methanol to yield Pazopanib hydrochloride.
WO '159 publication disclosed that use of sodium bicarbonate with specific particle size distribution of >250 μm or 50 to 150 μm is key element in condensation of compound of Formula A and Formula B to minimize the formation of Impurity of Formula I within the range of about 0.05-4.0%.

WO '159 publication also disclosed that use of potassium carbonate with specific particle size distribution D99 of >300 μm or D99 of <200 μm is key element in methylation of compound of Formula II to reduce the formation of Impurities of Formula 2, Formula 3 and Formula 4 within the range of about 0.05-3%.

Patent publication No. WO 2012/073254 (“the '254 publication”) disclosed a process for preparation of pazopanib hydrochloride, which involves condensation of 2,4-dichloropyrimidine of Formula B with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of a base like sodium bicarbonate and a solvent like ethanol to yield 5-(4-chloropyrimidin-2-yl-amino)-2-methylbenzenesulfonamide. The resultant compound was condensed with N-2,3-trimethyl-2H-indazole-6-amine of Formula D in an alcoholic solvent like ethanol. WO '254 publication also discloses process for purification of pazopanib hydrochloride from alcoholic solvent and water. The process disclosed in the '254 publication is schematically represented as follows:

Patent publication No. IN 2505/CHE/2011 disclosed a process for preparation of pazopanib, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dichloropyrimidine of Formula B in presence of sodium bicarbonate and a phase transfer catalyst like tetrabutyl ammonium bromide in a solvent like methanol to obtain N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine of Formula II. The resultant compound was methylated in presence of methyl iodide, potassium carbonate in a solvent like dimethylformamide to obtain compound of Formula m. The obtained Formula I was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of dimethylformamide and concentrated HCl to yield pazopanib hydrochloride.
Patent publication No. CN 103373989 (“the '989 publication”) disclosed a process for preparation of Pazopanib intermediate of Formula III by condensation of N-2,3-trimethyl-2H-indazole-6-amine of Formula D with 2,4-dichloropyrimidine of Formula B in presence of sodium bicarbonate and THF.

Patent publication No. WO 2014/97152 (“the '152 publication”) disclosed a process for preparation of Pazopanib hydrochloride starting from 2,3-dimethyl-6-nitro-2H-indazole.
The processes for preparation of pazopanib described in the above literature have certain drawbacks as it involves: a) use of specific predefined particles of bases like sodium bicarbonate and potassium carbonate, which involves additional process steps like milling, grinding etc, b) use of expensive phase transfer catalysts and c) multiple steps making the process quite expensive, particularly on large scale.
European Medicines Agency (EMA) public assessment report disclosed that pazopanib hydrochloride is a white to slightly yellow, non-hygroscopic, crystalline substance and the manufacturing process consistently produces pazopanib hydrochloride Form 1. However, the EMEA does not describe any particular characterization data for the disclosed polymorph Form 1.
PCT Publication No. WO 2011/058179 (“the '179 publication”) discloses pazopanib base crystalline Forms such as Form-I and Form-II and a process for its preparation; also disclosed characterization data of Form-I and Form-II by XRD, IR and melting point.
PCT Publication No. WO 2011/069053 (“the '053 publication”) discloses crystalline pazopanib base and crystalline pazopanib hydrochloride Forms such as Form-II, Form-III, Form-IV, Form-V, Form-VI, Form-VIII, Form-IX, Form-X, Form-XI, Form-XII, Form-XIII, Form-A, Form-G and also discloses crystalline Pazopanib dihydrochloride Forms such as Form-I, Form-XIV, Form-XV. The crystalline Forms reported in the PCT publication characterized by its XRD pattern.
IN Publication No. 3023/CHE/2010 discloses crystalline pazopanib dihydrochloride Form-I and crystalline pazopanib mono hydrochloride, process for it preparation and characterization by XRD of the same.
IN Publication No. 1535/CHE/2012 discloses crystalline pazopanib hydrochloride Form-SP and a process for its preparation; also disclosed characterization data of Form-SP by XRD, DSC and IR.
PCT Publication No (s): WO 2007/143483, WO 2007/064753, WO 2006/20564 and WO 2005/105094 as well as US Publication No. US 2008/0293691 disclose anhydrous and hydrated Forms of pazopanib hydrochloride and their process for preparation thereof.
IP.Com journal disclosure Number IPCOM000207426D discloses crystalline Form of pazopanib hydrochloride Form-R, which is characterized by XRD pattern.
Further, IP.Com journal disclosure Number IPCOM000193076D discloses crystalline Forms of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine of Formula III such as Form I and Form II along with characteristic data of XRD pattern.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound, like pazopanib, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence there remains a need for an improved process to prepare pazopanib or a pharmaceutically acceptable salt thereof and novel polymorphs of pazopanib or a pharmaceutically acceptable salt thereof, particularly pazopanib hydrochloride, which is cost effective, industrially viable, and provide pazopanib substantially free of aforementioned impurities.
The present invention provides an improved process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof, with improved purity and low levels of process impurities including genotoxic impurities as compared to the prior-art processes without restricting to base specific particle size.
The present invention also provides new polymorphic forms of the pazopanib hydrochloride, which are designated as pazopanib hydrochloride Form-L1, Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Form-L7, Form-L8 and Form-L9.
The present invention further provides novel polymorphic Forms of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine (Formula III), which is an key intermediate in the preparation of pazopanib. The new crystalline polymorphic Forms of Formula III have been designated as Form-K1, Form-K2, Form-K3 and Form-K4.